Cancer develops when abnormality in gene occurs by an action of radiation, ultra violet rays, carcinogen, virus, and the like. The number of deaths by cancer increases year by year, and cancer is currently the top cause of death in Japan. As means for such cancer therapy, antitumor agents, surgical operation, radiotherapy, immunotherapy, and the like are performed. However, among these, the therapeutic use of an antitumor agent is the most important as an internally therapeutic means. Major antitumor agents act on any of metabolism of a nucleic acid precursor, DNA synthesis, RNA synthesis, or protein synthesis. However, such metabolic processes occur in not only cancer cells, but also normal cells. Therefore, many antitumor agents act on not only on cancer cells, but also on normal cells, and consequently a variety of side effects develop.
In recent years, a new type of antitumor agent, called molecular targeting agent, has been introduced. This molecular targeting agent is a pharmaceutical agent designed to target a molecule specifically expressed in each cancer. Therefore, it is believed that a molecular targeting agent has higher specificity to cancer cells than conventional antitumor agents, and has fewer side effects. However, with regard to molecular targeting agents, although previous side effects are reduced, there are problems that new side effects are exhibited and alternatives of pharmaceutical agents are limited. Although the aforementioned antitumor agents were clinically used for the purpose of cancer therapy and prolonging the life of a cancer patient, there are still a number of unsolved problems including problems of side effects and the like as described above. Accordingly, it is recognized that the development of a novel antitumor agent is an important object in the future.
In recent studies, the existence of cancer stem cells (CSC) having self-replication competence has been revealed, the CSC is closely related to the malignant transformation of cancer. In nearly all of major types of cancer in human, such as breast cancer, colon cancer, lung cancer, hematological malignancy, and the like, CSCs are identified. A CSC and a conventional cancer cell differentiated from the CSC are significantly different in biological characteristics. A CSC is shown to be important in continuous proliferation of malignant tumor, metastasis and recurrence of cancer, and its resistance to an antitumor agent. Although Conventional therapy that targets conventional cancer cells accounting for most part of tumor lumps can reduce the size of a tumor, as long as a CSC is also targeted at the same time, a meaningful survival effect cannot be expected. Therefore, targeting a CSC is very promising as a new method to treat a cancer (Non Patent Literature 1). One of the characteristics of CSCs is to have replication competence. Reliable methods established as a method of measuring replication competence of a cell include measurement of cancer cell sphere-forming ability in non-adhesion state in the absence of serum (Non Patent Literature 2). A compound that inhibits not only the proliferation of a non-CSC cancer cell, but also cancer cell sphere-forming ability is possibly very useful as a novel antitumor agent.
(1) Non Patent Literature 3 discloses that the following quinone derivatives isolated from the extract of a plant of the Tabebuia genus in the Bignoniaceae family have antitumor activity:
[wherein R1, R2, and R3 are hydrogen atoms; R1 and R3 are hydrogen atoms, and R2 is a hydroxyl group; R1 is a hydroxyl group, and R2 and R3 are hydrogen atoms; R1 and R2 are hydrogen atoms, and R3 is COCH3; or R1 and R2 are hydrogen atoms, and R3 is COC(CF3)(OCH3)C6H5].
(2) Patent Literature 1 describes the following compound having antitumor activity and suppressing cancer cell sphere-forming ability:
[wherein X is O or S, R1 is a hydrogen atom, a halogen atom, a cyano group, a nitro group, a trifluoromethyl group, a trifluoromethoxy group, an optionally substituted alkyl group, or the like, R3 is a hydrogen atom, a cyano group, an optionally substituted alkyl group, or the like, R7 is a hydrogen atom, a halogen atom, a cyano group, a nitro group, an optionally substituted alkyl group, or the like, n is 1 to 4, with the proviso that when R3 is not an amino group, R7 is not a hydrogen atom and at least one of R1 and R7 is a halogen atom, an aryl group, or an optionally substituted aryl group].
(3) Patent Literature 2 describes the following compound as a hydrophobic prodrug for oral administration that is administered as a non-crystalline compound:
[wherein n is 0 to 4, each R1 is independently halogen, —NO2, —CN, —OR, —SR, —N+(R)3, —N(R)2, —C(O)R, CO2R, or the like, each of R2 and R3 is independently a hydrogen atom, —S(═O)2ORa, —P(═O)ORaORb, or —C(═O)Rc, each of Ra and Rb is independently a hydrogen atom, sodium, potassium, an amine cation, a C1-12aliphatic, or the like, Rc is a hydrogen atom, —N(R)2, —OR, —SR, a C1-12aliphatic, or the like, R4 is independently a hydrogen atom, halogen, —NO2, —OR, —SR, —N(R)3, —N(R)2, —C(O)R, CO2R, or the like, R5 is independently halogen, —NO2, —CN, —OR, —SR, —N+(R)3, —N(R)2, —C(O)R, CO2R, or the like, and each R is independently a hydrogen atom, or an optionally substituted group selected from a C1-12aliphatic, a 3- to 14-membered carbocycle, or a 3- to 14-membered heterocycle, a 6- to 14-membered aryl ring, or a 5- to 14-membered heteroaryl ring, with the proviso that (a) when each of R2 and R3 is acetyl, R1 is not acetoxy, (b) when each of R2 and R3 is acetyl and R4 is ethoxycarbonyl, R5 is not 2-oxo-propyl, (c) when each of R2, R3, and R5 is acetyl, either of R1 or R4 is not hydrogen].
(4) Patent Literature 3 describes the following compound exhibiting antitumor activity against various drug-resistant cancer cells:
[wherein n is 0 to 4, each R1 is independently halogen, —NO2, —CN, —OR, —SR, —N+(R)3, —N(R)2, —C(O)R, CO2R, or the like, each of R2 and R3 is independently a hydrogen atom, —S(═O)2ORa, —P(═O)ORaORb, —C(═O)Rc, each of Ra and Rb is independently a hydrogen atom, sodium, potassium, an amine cation, a C1-12aliphatic, or the like, Rc is a hydrogen atom, —N(R)2, —OR, —SR, a C1-12aliphatic, or the like, R4 is independently a hydrogen atom, halogen, —NO2, —OR, —SR, —N(R)3, —N(R)2, —C(O)R, CO2R, or the like, R5 is independently halogen, —NO2, —CN, —OR, —SR, —N+(R)3, —N(R)2, —C(O)R, CO2R, or the like, and each R is independently a hydrogen atom, or an optionally substituted group selected from a C1-12aliphatic, a 3- to 14-membered carbocycle, or a 3- to 14-membered heterocycle, a 6- to 14-membered aryl ring, or a 5- to 14-membered heteroaryl ring].
(5) Patent Literature 4 describes the following compound as a hydrophobic prodrug for parenteral administration that is administered as aqueous nanoparticle suspension:
[wherein n is 0 to 4, each R1 is independently halogen, —NO2, —CN, —OR, —SR, —N+(R)3, —N(R)2, —C(O)R, CO2R, or the like, R2 is independently a hydrogen atom, halogen, —NO2, —OR, —SR, —N(R)3, —N(R)2, —C(O)R, CO2R, or the like, each of R3 and R5 is independently optionally substituted a C1-21aliphatic, R4 is independently halogen, —NO2, —CN, —OR, —SR, —N+(R)3, —N(R)2, —C(O)R, CO2R, or the like, and each R is independently a hydrogen atom, or an optionally substituted group selected from a C1-12aliphatic, a 3- to 14-membered carbocycle, or a 3- to 14-membered heterocycle, a 6- to 14-membered aryl ring, or a 5- to 14-membered heteroaryl ring].
Generally, for most hydrophobic prodrugs to be enzymatically converted to an activated form, since interspecies difference and individual difference in conversion to an activated form are observed, a problem of drug concentration estimation in clinical practice occurs (Non Patent Literature 4). A prodrug for oral administration described in Patent Literature 2, after administration, is affected by a first-pass effect in a small intestine and a liver, which causes interspecies difference. Even in the case of an intravenously-administrable prodrug for parenteral administration described in Patent Literature 4, although it is not affected by a first-pass effect in a small intestine and a liver, it is converted to an activated form by an in vivo enzyme, esterase, and accordingly interspecies difference and individual difference may be observed in conversion to an activated form.